Since at least the 1920s, the analysis of blood based upon the sedimentation or separation of erythrocyte cells from blood plasma has been extensively undertaken. Two classic sedimentation techniques are most commonly employed, namely, the Wintrobe method and the Westergren method. These techniques each utilize observation and recording of the settling of erythrocyte or red cells in a blood specimen from the relatively clear white cell-containing plasma fluid. As the red cells settle, a separation boundary between the erythrocyte cells and clear plasma occurs and drops or moves down the tube with continued red cell settling.
During settling, the erythrocyte cells periodically stack in structures known as "rouleaux" and start to gravitate through the fluid plasma toward the bottom of the settling tube. The relative movement between the rouleaux and plasma causes the rouleaux to breakdown and setting to be slowed. This process is repeated with time and affects the rate at which the separation boundary settles. The amount or drop of the separation boundary in a predetermined time interval, for example one hour, has been referred to as the "settling rate" of the blood sample. This settling rate has been found to have a significant, although not very specific, correlation with the presence of inflammatory diseases and/or conditions.
While classic sedimentation rate measurements provide some useful information as to the presence or absence of inflammatory conditions in a patient, they inherently have been incapable of specifically identifying conditions or diseases, and they have not been very useful in tracking the progress of, or degree of involvement in, the disease.
Attempts have been made to gain more useful data from blood specimen settling or sedimentation. Additionally, various apparatus have been employed to attempt to automate the sensing and recording of erythrocyte cell sedimentation. The attempts to automate the classic sedimentation rate measurement techniques have generally proceeded along the same line as the original manual approach, namely, to employ an apparatus which transmits radiation, usually radiation in the visible light range, through the test specimen. Various recording and tracking heads have been employed in which the movement of the head occurs when there is a change from an inability to transmit light through the sample to an ability to transmit light. This change occurs when the separation boundary drops down below the position of the light beam emitting and sensing apparatus. Typical of such blood sedimentation apparatus and methods are the devices shown in U. S. Pat. Nos. 2,725,782, 2,982,170, 3,261,256, 3,288,019, 3,422,443, 3,474,458, 3,604,924, 3,631,513, 3,715,761, 3,844,662, 3,952,579 and 4,118,974.
It has been recognized that a single measurement taken one hour or two hours after the specimen is placed in the settling tube only provides one or two points on the "settling curve". Thus, the goal of automating the recording of sedimentation of erythrocyte cells was in part to develop an entire settling curve in the hope that the curve would provide more useful data that could be correlated to inflammatory conditions.
Study of the sedimentation curves produced by various continuous recording apparatus, however, has revealed that accuracy in the correlation of inflammatory conditions with settling curve shapes has not been possible. Diagnosis of inflammatory conditions using the complete settling curve for erythrocyte cells over a one, or even a two hour, settling period has lacked the reliability necessary for a sound diagnosis.
The suggestion is also found in the prior art that the instantaneous rate of settling, or the derivative of the settling curve (change in height divided by the change in time), may yield data which are more helpful and more easily correlated to permit diagnosis of inflammatory conditions than the settling curve itself. Thus, in U.S. Pat. No. 4,041,502 to Williams et al. and a companion article entitled "An Automatic Sedimentimeter" in Biorheoloqy (Vol. 14, pp. 145-149, 1977) Misiaszek, Williams, Stasiw and Cerny, an apparatus and method for discrete recording of both the settling curve and the first derivative or instantaneous settling rate of the settling curve are disclosed.
In the sedimentimeter of the Williams et al. patent, a light-emitting diode is mounted next to a vertical settling tube on a movable tracking head. The LED transmits a light beam through the tube to a photodiode detector positioned on the tracking head on the other side of the specimen. When the photodiode detector cannot detect the beam from the LED, the tracking head is below the separation boundary between the erythrocyte cells and fluid plasma. As the separation boundary drops to a position below the beam from the LED, the photodiode detector detects the beam and thereby senses the passage of the separation boundary beyond the current beam position.
The Williams et al. tracking head is moved down the tube by a stepping motor. The LED emits static or constant radiation which continuously irradiates the photodiode through the tube, and if the photodiode detector senses light from the LED above a predetermined threshold level, the stepping motor is actuated to drop the tracking head. The system includes a clock and logic circuit which operates the stepping motor for a period of time sufficient to cause the amount of light sensed by the photodiode detector to drop below a certain level, at which point the stepping motor ceases operation. A recording circuit samples data as to the time which the motor has operated every 15 seconds and records the length of time of operation of the stepping motor for each 15 second interval to thereby provide a record of the motion of the tracking head and the separation boundary.
In order to obtain further data for correlation with diseases, in the Williams et al. patent the approximate slope of the sedimentation curve or the instantaneous rate of sedimentation also is calculated. This is accomplished by determining the drop in distance of the tracking head for each 15 second interval of time over the entire settling period, usually one hour.
The instantaneous settling rate or first derivative of the settling curve which is produced by the Williams et al. apparatus was thought to produce data that would be more likely to be able to be correlated with inflammatory conditions. For example, the first derivative or slope curve might yield information as to the formation and breakdown of rouleaux, which may be an indication of the presence or absence of an inflammatory condition. Thus far, however, the hoped-for correlation of the settling rate data with inflammatory conditions has not been realized, and erythrocyte cell sedimentation studies still have not been proven to be capable of reliable disease diagnosis.
Other articles in the technical literature since the Williams et al. patent which discuss erythrocyte cell sedimentation and the continuing limited usefulness of sedimentation rates as a diagnostic tool include:
"The Age-Related Hemorheological and Osmotic Properties of Human Blood," by Cerny et al., Biorheology, Vol. 74, No. 182, pp. 85-89 (1978);
"The Erythrocyte Sedimentation Rate of Blood Reconsidered," by Merrill et al., Biorheology, Vol. 74, No. 182, pp. 90-95 (1978); PA1 "Optical Method for Haematocrit Determination," by Singh et al., Medical & Biological Engineering & computing, vol. 20, pp. 527-528 (July, 1982); PA1 "The Erythrocyte Sedimentation Rate Time Curve: Critique of an Established Solution," by Dorrington et al., Biomechanics, Vol. 16, No. 1, pp. 99-100 (1983); and PA1 "Erythrocyte Sedimentation Rate--From Folklore to Facts," by Bedell et al., The American Journal of Medicine, Vol. 78, pp. 1001-1009 (June, 1985).
The white cell-containing plasma above the settled erythrocyte cells has largely been ignored as a source of usable sedimentation-based data. In patients having a significant one-hour erythrocyte settling rate, for example, over about 7 millimeters, however, bands or layers of white cells can be seen to occur above the settled red cells. This white cell banding suggests that sedimentation is occurring in connection with the different types of white cells. While various clinical tests have been devised for white cells, they have not previously included attempts to obtain data useful in the diagnosis of inflammatory conditions from white cells based upon their settling and banding characteristics.
Accordingly, it is an object of the present invention to provide a process and apparatus which is capable of a sufficiently accurate determination of the instantaneous settling rate of erythrocyte cells to enable the diagnosis of specific inflammatory conditions.
Another object of the present invention is to provide an erythrocyte sedimentation tracking process and apparatus in which data is sampled when changes in the cell settling rate actually occur, rather than at timed intervals, to enable sensing of the occurrence of changes in sedimentation.
Another object of the present invention is to provide an erythrocyte sedimentation tracking process in which changes in red cell sedimentation which are affected by rouleaux formation and rouleaux breakdown, and protein-protein interaction can be recorded and used to correlate settling with inflammatory conditions.
A further object of the present invention is to provide an erythrocyte sedimentation-based process for diagnosing inflammatory conditions in which changes in settling characteristics of erythrocyte cells as they settle past a sensing zone are determined.
Still another object of the present invention is to provide an erythrocyte sedimentation instrument and process which is more sensitive to changes in settling rates and provides more data for the statistical analysis necessary for correlation to inflammatory conditions.
A further object of the present invention is to porvide an instrument and process which senses and samples a characteristic (preferably reflectivity) of settling of fluid plasma containing white cells and enables correlation of a sampled fluid plasma characteristic to inflammatory conditions.
Another object of the present invention is to provide an apparatus and process for the tracking of instantaneous settling rates of erythrocyte cells which is self-calibratable to each test specimen of blood for improved accuracy and higher correlation of instantaneous sedimentation rates with inflammatory conditions.
Still a further object of the present invention is to provide a process for the use of repetitive patterns occurring in one or all of: erythrocyte instantaneous settling rates, white cell reflectivity scans, erythrocyte reflectivity scans, and erythrocyte reflectivity immediately after a settling increment occurs, in the identification of inflammatory conditions.
Another object of the present invention is to provide a blood cell sedimentation apparatus which is relatively simple and inexpensive to construct, operate and maintain.
A further object of the present invention is to provide a cell sedimentation apparatus which is capable of obtaining useful data from both red cell and white cell sedimentation.
Still another object of the present invention is to provide a method for obtaining useful red and white cell sedimentation data which can be automated and produces data suitable for computer analysis and computer correlation to inflammatory conditions.
The apparatus and process of the present invention have other objects and features of advantage which will become apparent from or are set forth in more detail in, the accompanying drawing and the following description of the Best Mode of Carrying Out the Invention.